There is a rapidly growing body of evidence that Muller glia are a source of retinal progenitors to mediate neural regeneration. Many studies have demonstrated that Muller glia can become proliferating progenitor cells in the retinas of different vertebrate species. Nearly all reports have studied Muller glia-derived progenitors in acutely damaged retinas. However, little is known about the mechanisms that stimulate neurogenesis from Muller glia-derived progenitors in undamaged retinas or retinas undergoing slow, progressive degeneration. Furthermore, the regeneration of retinal neurons in warm-blooded vertebrates is limited compared to that seen in cold-blooded vertebrates. Therefore, the identification of the secreted factors and signaling pathways that permit and/or stimulate neural regeneration from Muller glia-derived progenitors is crucially important to developing new therapies to treat degenerative diseases of the human retina. We have obtained preliminary data indicating that signaling through the glucocorticoid receptor (GCR), p38 MAPK and signals derived from other types of retinal glia significantly impact the neurogenic potential of Muller glia. We will investigate the coordinated activity of different types of retinal glia including the Muller glia, microglia and the recently described Non-astrocytic Inner Retinal Glia-like (NIRG) cells. We have identified the NIRG cells as a distinct type of glial cell that is present in retina of birds, canines and primates. We believe that the NIRG cells influence the ability of Muller glia to become retinal progenitors. We expect that the completion of the experiments described in this proposal will provide significant new information regarding different signaling pathways, secreted factors, and how the microglia and NIRG cells influence the formation of Muller glia-derived retinal progenitors. Identification and understanding of the mechanisms that enhance the neurogenic potential of Muller glia is required to develop new therapies for sight-threatening diseases, such as glaucoma and macular degeneration that involve the loss of retinal neurons. PUBLIC HEALTH RELEVANCE: A thorough understanding of the mechanisms that regulate the functions of glial cells is crucially important to the development of new therapies to treat sight-threatening diseases of the retina. Retinal Muller glia is known to have the potential to become neurogenic progenitor cells. Identification and understanding the mechanisms that regulate the neurogenic potential of Muller glia-derived progenitors is key to developing neuron-replacement therapies for the retina. This proposal seeks to identify important glial interactions and signaling pathways that enhance the ability of Muller glia to become proliferating progenitors and produce new functional neurons. A goal of this project is to study defined molecular mechanisms and signaling pathways that regulate glial functions related to reactivity, proliferation, and neuronal regeneration. The findings produced by the proposed studies will provide valuable new insights into the factors and signaling mechanisms that regulate inter-glial communication and glia- mediated neuronal regeneration.